CXCL12/CXCR4 promotes motility and proliferation of glioma cells

Carmo, Anália do; Patricio, Inês; Cruz, Maria Teresa; Carvalheiro, Helena; Oliveira, Catarina; Lopes, María Celeste

doi:10.4161/cbt.9.1.10342

Cited by 66 publications

(43 citation statements)

References 32 publications

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“…These types of experiments in transfected cells have limited import, but relevant findings utilizing various transformed cell lines have been reported. For example, glioblastoma cells show SDF-1␣ dose-dependent proliferation, which is reduced by AMD3100 pretreatment (57)(58)(59). Interestingly, CXCR7 confers a growth advantage to the breast tumor cell line MDA MB435s, which was seen as an increase in the live cell count, but not necessarily the total cell count, an effect that can be reduced with the specific CXCR7 ligand CCX754 (12).…”

Section: Discussionmentioning

confidence: 99%

CXCR7/CXCR4 Heterodimer Constitutively Recruits β-Arrestin to Enhance Cell Migration

Décaillot¹,

Kazmi

Lin

et al. 2011

Journal of Biological Chemistry

305

328

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G protein-coupled receptor hetero-oligomerization is emerging as an important regulator of ligand-dependent transmembrane signaling, but precisely how receptor heteromers affect receptor pharmacology remains largely unknown. In this study, we have attempted to identify the functional significance of the heteromeric complex between CXCR4 and CXCR7 chemokine receptors. We demonstrate that co-expression of CXCR7 with CXCR4 results in constitutive recruitment of ␤-arrestin to the CXCR4⅐CXCR7 complex and simultaneous impairment of G i -mediated signaling. CXCR7/CXCR4 co-expression also results in potentiation of CXCL12 (SDF-1)-mediated downstream ␤-arrestin-dependent cell signaling pathways, including ERK1/2, p38 MAPK, and SAPK as judged from the results of experiments using siRNA knockdown to deplete ␤-arrestin. Interestingly, CXCR7/CXCR4 co-expression enhances cell migration in response to CXCL12 stimulation. Again, inhibition of ␤-arrestin using either siRNA knockdown or a dominant negative mutant abrogates the enhanced CXCL12-dependent migration of CXCR4/CXCR7-expressing cells. These results show how CXCR7, which cannot signal directly through G protein-linked pathways, can nevertheless affect cellular signaling networks by forming a heteromeric complex with CXCR4. The CXCR4⅐CXCR7 heterodimer complex recruits ␤-arrestin, resulting in preferential activation of ␤-arrestin-linked signaling pathways over canonical G protein pathways. CXCL12-dependent signaling of CXCR4 and its role in cellular physiology, including cancer metastasis, should be evaluated in the context of potential functional hetero-oligomerization with CXCR7.

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Section: Discussionmentioning

confidence: 99%

CXCR7/CXCR4 Heterodimer Constitutively Recruits β-Arrestin to Enhance Cell Migration

Décaillot¹,

Kazmi

Lin

et al. 2011

Journal of Biological Chemistry

305

328

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“…Cells were plated in six multi-well plates and incubated with TMZ, wortmannin, U-0126 and rapamycin for 24 and 48 h. At the end of the incubation period, cells were centrifuged at 1,500 rpm for 10 min, the culture medium was discarded and the pellet was resuspended in a solution of 70% ethanol and maintained overnight. The cells were then centrifuged at 1,500 rpm for 10 min, the pellet was resuspended and incubated for 1 h in the dark, at room temperature, in a solution of PBS containing 10 µl/ml PI and 10 µl/ml RNAse (13 Study of protein expression. Cells incubated with TMZ for 24 and 48 h were centrifuged at 1,500 rpm for 10 min at 4˚C.…”

Section: Methodsmentioning

confidence: 99%

Effect of temozolomide on the U-118 glioma cell line

et al. 2011

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Abstract. Glioblastomas (GBM) are the most lethal subtype of astrocytomas, with a mean patient survival rate of 12 months after diagnosis. The gold standard treatment of GBM, which includes surgery followed by the combination of radiotherapy and chemotherapy with temozolomide (TMZ), increases the survival rate to 14.6 months. The success of TMZ appears to be limited by the occurrence of chemoresistance that allows glioma cells to escape from death signaling pathways. However, the mechanism of TMZ action is yet to be clarified although some controversial results have been reported. Therefore, our aim was to evaluate the occurrence of apoptosis and autophagy in glioma cells treated with TMZ and to correlate TMZ action with the survival pathways Pi3K/ Akt and ERK1/2 MAP kinase. Cell proliferation was evaluated by incorporation of bromodeoxyuridine. Apoptosis was studied by flow cytometry as well as by fluorescence confocal microscopy in order to evaluate the sub G0/G1 percentage of cells and chromatin condensation. The expression of the autophagy-associated protein, LC3, as well as Akt and ERK1/2 was performed by Western blotting. In TMZ-treated GBM cells the expression of LC3, the autophagy-associated protein was increased and only a reduced percentage of cells underwent apoptosis. In addition, we showed that the phosphorylation status of Pi3K/Akt and ERK1/2 MAP kinase was maintained during the treatment with TMZ, suggesting that glioma cells escape from TMZ-induced cell death due to these signaling pathways. The chemoresistance of U-118 cells to TMZ was partially eradicated when cells were simultaneously treated with specific inhibitors of Pi3K/Akt and ERK1/2 MAP kinase signaling pathways and TMZ. Therefore, we hypothesized that in order to induce glioma cell death it is essential to evaluate the activation of the survival pathways and establish a combined therapy using TMZ and inhibitors of those signaling pathways.

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“…Activation of the chemokine receptor CXCR4 through its ligand CXCL12 has been shown to induce migration and/or survival in multiple human cancer cell lines. 1 A prognostic role of CXCR4 overexpression has been described in many neoplasms, including renal cancer, 2,3 brain tumors, 4 neuroblastoma, 5 colorectal cancer, 6 prostate cancer, 7 melanoma, 8 pancreatic tumor, 9 lung cancer 10 and ovarian cancer. 11 The CXCR4/CXCL12 pathway may be a reasonable target in renal cancer given that overexpression of CXCR4 has been identified in RCC tumor samples.…”

Section: Introductionmentioning

confidence: 99%